Primary immunodeficiency diseases represent an unique model to study the development on the human immune system. For several of these diseases, the only currently available therapy is allogeneic bone marrow transplantation, which may result in incomplete reconstitution of immunity and may be associated with severe graft versus host reactions. Genetic correction of autologous hematopoietic stem cells would thus represent a beneficial alternative form of treatment for those immunodeficiencies of known genetic origin. We are developing pre-clinical models of gene therapy for several immunodeficiencies including X-linked severe combined immunodeficiency (X-SCID), JAK3-SCID, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, IL-12 receptor deficiency, and others. In these experiments, retroviral or non-viral vectors are being used to correct the genetic aberration responsible for each specific disorder and to express the missing or mutated protein in cells obtained from affected patients. For those immunodeficiencies for which animal models are available, experiments of genetic correction of bone marrow hematopoietic progenitors are performed to verify in vivo safety and efficacy of this approach.